Transfusion-associated graft-versus-host disease

(TA-GVHD)
Definition:
Graft-versus-host disease (GVHD) is a rare complication that can
develop 4 to 30 days after a blood transfusion. Recognition is often
delayed because nonspecific symptoms are attributed to the
patient’s underlying diagnosis.

TA-GVHD is a delayed reaction and usually presents 10 -12 days

after transfusion.
Who’s at risk?
 Immunocompetent patient transfused with HLA
haploidentical product (blood relative)
 Neonatal exchange transfusions
 Severely immunocompromised patients

Donor cells attack

Hematopoietic cells  refractory pancytopenia
Other organ systems: Fever, enterocolitis, rash, hepatitis

Usually fatal: 90-100%

When to suspect this adverse reaction?

TA-GVHD is extremely rare and transfused patients present with fever,

rash and diarrhoea commencing 1-2 weeks post-transfusion. Laboratory
findings include pancytopenia and liver function abnormalities.

TA-GVHD leads to profound marrow aplasia with a mortality rate >90%.

Death typically occurring within 1–3 weeks of first symptoms, most
commonly due to overwhelming infections.

Symptoms include fever, rash, diarrhea, hepatitis, and marrow aplasia with
subsequent infection and bleeding; most cases are fatal.
Pathogenesis of TA-GVHD:

A-GVHD is associated with the transfusion of (immunologically

competent donor) lymphocytes into recipients.
TA-GVHD seen mainly in:
1. When the recipient is immunodeficient is at higher risk of TA-GVHD
2. When there is a specific type of partial human leukocyte antigen
(HLA) matching between the donor and recipient (Partial HLA
matching’ recipients of blood who are heterozygous for an HLA
haplotype for which the donor is homozygous. In this setting, the
recipient does not recognize the donor lymphocytes as being
foreign, since the only HLA antigens seen by the host lymphocytes
are shared by the recipient. However, the reverse is not true, since
the donor lymphocytes view the host's tissues as foreign, leading to
immunologic activation and ta-GVHD.
The result: the donor lymphocytes engraft in the recipient and initiate
a cellular immune response against the host.
Diagrammatic explanation of potential HLA incompatibility between donor and recipient. In the setting of
blood transfusion where the donor is homozygous for 1 of the HLA haplotypes of the recipient, the recipient
sees the donor as self but the donor sees the recipient as foreign, and an immune attack is initiated against
the recipient.
BILLINGHAM’S CRITERIA FOR DEVELOPMENT OF GVHD:

• The graft must contain immunologically competent cells

• There must be antigenic differences between the donor and the
recipient
• The recipient must be unable to mount an effective immunologic
response to eradicate the transplanted immunologically competent
cells.

Rarely immunocompetent recipients can also develop TA-GVHD.

 Usual causes?
This normally happens to immunodeficient recipients whose immune system
is unable to recognise the transfused T lymphocytes as foreign. These
lymphocytes engraft in the recipient and react against the host.
Factors for developing TA-GVHD

1) Degree of recipient immunodeficiency

Inability to reject the donor T cells is the main factor.

2) Degree of population’s genetic diversity

The estimated risk of developing TAGVHD
In Japan - 1:874
In France – 1:16,835

3) No. of viable T cells in transfusion Minimum no. of leukocytes required

to cause the disease is unknown.
Some studies indicate that fewer than 1 to 5x105 T cells/kg recipient body
weight are safe.
What are Implicated blood products in Ta-GVHD
It may occur after transfusion of
• Whole blood
• Packed red blood cells
• Platelets
• Granulocytes
• Unfrozen plasma

But not after

• Fresh frozen plasma
• Cryoprecipitate
Clinical Presentation:
Ta-GVHD develops 4 to 30 days after blood transfusion. Patients
typically present with fever and an erythematous, maculopapular
rash which often progresses to generalized erythroderma and, in
extreme cases, to toxic epidermal necrolysis.

Other symptoms include anorexia, vomiting, abdominal pain (most

often in the right upper quadrant), profuse diarrhea (up to 7 to 8
L/day), and cough.

The main laboratory findings are pancytopenia (which reflects a

strikingly hypocellular marrow), abnormal liver function tests, and
electrolyte abnormalities induced by diarrhea.
Investigation

1. Diagnosis is normally made on skin biopsy and occassionally on

liver or bone marrow biopsies. Skin biopsy , reveals vacuolization
of the basal layer and a histiocytic infiltrate, which is also seen in
the aplastic bone marrow. Skin biopsy occasionally shows an
almost pathognomonic finding — satellite dyskeratosis, which is
characterized by single, dyskeratotic cells accompanied by
lymphocytes.

1. The definitive diagnosis:Chimerism to detect circulating

lymphocytes of different (HLA) phenotype from host tissue cells, to
prove that they came from the donor.
DIFFERENTIAL DIAGNOSIS:
1. Infection:Viral infections, including human immunodeficiency virus (HIV),
hepatitis B virus (HBV), and hepatitis C virus (HCV): Like ta-GVHD, these
viral infections may cause fever, rash, hepatic dysfunction, and bone
marrow failure.
2. Drug reaction: Patients with underlying hematologic conditions who
require transfusion are also often receiving a variety of medications that
may cause systemic reactions.
3. Liver failure – Liver failure can be caused by certain medications, either
by dose-dependent hepatotoxicity or an idiosyncratic reaction. patients
with liver failure often do not have rash or pancytopenia; skin biopsy or
liver biopsy will show typical findings of the specific disease.
4. Hemophagocytic lymphohistiocytosis:
TREATMENT AND PREVENTION
What to do?
• poorly responsive to any available form of therapy and is almost
always a fatal complication.
• Treatment is supportive. Often corticosteroids and cytotoxic agents
are used but are largely ineffective and therefore, prevention is
crucial.
• Agents that have been tried without substantial success include
corticosteroids, azathioprine, antithymocyte globulin, methotrexate,
and cyclosporine.
• For patients at risk, it is critical to gamma irradiate cellular blood
components. Leucocyte depletion is not sufficient for prevention.
• Two agents shown to have some success treating, rituximab and
ibrutinib, have yet to be evaluated in ta-GVHD.
Prevention
• Protects patient from Transfusion Associated Graft Versus Host Disease
(TA-GVHD)
• Inactivates lymphocyte division in blood product
• 2,500 cGy (cesium) applied to blood product
• Patients that need irradiated blood products:
• Fetusus / newborns (usually up to 4 months of age)
• Bone marrow transplant patients / candidates
• Hematological malignancy
• Congenital immunodeficiency (DiGeorge Syndrome, etc)
• Blood relative blood donations.

• Leukodepletion — Third and fourth generation leukodepletion filters, which

can produce a three to five log reduction in white cell number, can
theoretically reduce the incidence of ta-GVHD.
Comparison of GVHD Following Hematopoietic Stem Cell
Transplantation with Transfusion-Associated GVHD
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